In certain instances, human pharmacogenetic disorders cause individuals to react very differently to the same dose of the same drug. The teratogenic, carcinogenic, or toxic effects of certain drugs and other foreigh compounds also may reflect important genetically mediated differences among individuals. Accordingly, our laboratory has developed experimental model systems for studying drug metabolism with recombinant DNA technology, in cell culture, and among inbred strains of mice. The Ah locus regulates the induction of a small subset of all the multiple cytochromes P-450. The Ah receptor(s) controls this induction process. We have isolated and characterized the genomic Pl-450 gene and cDNA clones for P2-450 and PGamma-450. The mouse Pl-450 clone cross-hybridizes to the corresponding gene from rat, rabbit and human. With such clones we hope to understand the mechanisms of P-450 induction by drugs, to gain insight into the evolution of P-450 (present in plasmids and all eukaryotes), and to develop sensitive tests to determine clinically who is at increased risk for various drug-induced birth defects, other forms of drug toxicity, and environmentally-caused malignancies.